The overall goal of this project is to identify patterns of brain function that contribute to or result from dependence on drugs, and to suggest leads in the development of new treatment methods. Our research strategies involve the use of positron emission tomography (PET) to evaluate the effect of various drugs of abuse and cognitive activation on brain activity using cerebral metabolic rates for glucose using [F-18]fluorodeoxyglucose and regional cerebral blood flow using [O-15]-water, receptor occupancy [C-11]raclopride and and magnetic resonance imaging (MRI) to evaluate structural sequelae of drug abuse. [unreadable] To understand the pathophysiology of drug craving, it is essential to elucidate the neural substrates of drug craving. Although previous studies have linked dopamine to aspects of craving, there is no direct evidence that dopamine is released during drug craving behavior. Using [C-11]raclopride and PET, we measured extracellular dopamine activity. Subjects were scanned while watching and listening to neutral cues, followed by a second scan during presentations of cocaine cues. Dopamine activity was expressed using the percentage change in raclopride binding potential, which we used as a measure of dopamine release. Dopamine release was significantly greater in the right anterior putamen of participants who reported craving than in those who did not. Further, the intensity of craving was positively correlated with dopamine release in the left posterior putamen. These results provide the first direct evidence that extracellular dopamine release in human dorsal striatum increases proportionately with subjective increases in cocaine craving. [unreadable] Methadone maintenance is the primary treatment for opiate addiction, but controversy surrounds the merits of its use in long-term treatment. Fifteen methadone-free (6-24 months) opiate abusers, twelve opiate abusers receiving methadone maintenance (stable dose over 6 months), and thirteen control subjects participated in this study. Methadone-withdrawn subjects had lower relative metabolic activity measured by [F-18]fluorodeoxyglucose and PET than control subjects in bilateral perigenual and the left middle cingulate gyrus. In contrast, methadone-maintained subjects exhibited lower relative activity (vs. control) in the left insula, the thalamus, and the left inferior parietal lobule; however, they exceeedded control aactivity in the perigenual anterior cingulate gyrus and the right inferior parrietal lobule. Measures of depression covaried positively with relative activity in the left perigenual and mid-cingulate gyrus in methadone-withdrawn subjects; analogous associations in control subjects covaried negatively. Methadone-maintained subjects exhibited negative covariance between state measures of depression and relative activity in the right inferior parietal lobule and the right perigenual anterior cingulate, and between trait measures of depression and relative activity in the left inferior parietal lobule. Methadone maintenance ameliorates functional abnormalities in the neural circuitry sub-serving negative affective states, but depresses brain function in some regions of high opiate receptor density. [unreadable] We demonstrated that heavy marijuana users have performance deficits on the Iowa decision-making task, but not on the Stroop conflict task when compared to non-users. A sample of heavy marijuana users was found to have altered brain tissue composition (gray matter and white matter) in the hippocampa region and precentral gyrus on structural MR images compared to non-users using voxel-based morphometry.